Several discrete strategies have been suggested to prevent or reduce microbial resistance to antimicrobials, including optimal use of the agents (also known as good stewardship); control, removal, or restriction of antimicrobials; use of antimicrobials in combination; and rotational or cyclic use of antimicrobials. The latter strategy is attractive because it periodically removes from the institutional environment certain classes or specific agents that could induce or select resistance. Hospitalwide studies of aminoglycoside substitution employed from the late 1970s through the early 1990s, although not originally intended to test cycling or rotation of aminoglycosides, serendipitously provided data that may be useful in designing future studies. In particular, one 10-year study at the Minneapolis Veterans' Affairs Medical Center (MVAMC) rotated amikacin and gentamicin use over cycles of 12 to 51 months' duration. Significantly reduced resistance to gentamicin was found when amikacin was used, but resistance to gentamicin returned with the first gentamicin recycle. This was followed by reintroduction of amikacin a second time with decreased resistance to gentamicin and, finally, a second reintroduction of gentamicin without resistance to it recurring. Thus, some evidence of proof of principal can be garnered, albeit subject to considerable criticism. Critical examination of the design of the aminoglycoside rotation study and the unforeseen pitfalls is provided as a 13-element guidance list for design of future rotational studies. Rotational usage practices are likely to be most appropriate for drugs active against gram-negative bacilli because of the wide choices available for rotation. Future availability of new agents active against resistant gram-positive organisms will present the opportunity to cycle these agents as vancomycin substitutes. Careful monitoring of clinical outcomes and resistance will be required. Multicenter controlled trials that follow carefully designed protocols are most likely to produce statistically significant and clinically meaningful results.

Bacterial resistance to antibiotics continues to be a problem, in spite of increased knowledge of resistance mechanisms. Due to the multifactorial nature of bacterial resistance, studies that evaluate the association between antimicrobial exposure and emergence of resistance may fail to find a relationship unless other factors, in particular the association between patient-pathogen pharmacokinetics (PK) and pharmacodynamics (PD) and the emergence of bacterial resistance, are evaluated as well. It has been hypothesized that, in conjunction with good infection control practices, cycling of antimicrobial agents may prove to be effective in reducing resistance emergence.

There is some indication that there may be a relationship between the level of antibiotic exposure and the probability of emergence of bacterial resistance. As shown in our companion article in this supplement, factors associated with ciprofloxacin resistance in Pseudomonas aeruginosa included increased length of stay prior to isolation, exposure to ciprofloxacin, and respiratory tract site of bacterial isolation. However, in patients who received ciprofloxacin therapy, when exposure was at an area under the 24-hour inhibitory concentration curve (AUIC24)>110 (μg·h/mL)/μg/mL, resistance was decreased to 11%, a rate similar to that seen in respiratory isolates not exposed to ciprofloxacin (7%).

While the length of time the patient spends in the hospital and the site of infection cannot be controlled, by using PK and PD principles for dosing of ciprofloxacin, the emergence of ciprofloxacin resistance in P aeruginosa may be reduced. Prospective antibiotic-cycling studies may help to determine not only the impact of antibiotic cycling on the institution's antibiogram but also, through the use of PK and PD principles, may help to determine appropriate dosing schedules for antibiotics in order to reduce the probability of emergence of bacterial resistance.

Cycling of currently available antibiotics to reduce resistance is an attractive concept. For cycling strategies to be successful, their implementation must have a demonstrable impact on the prevalence of resistance determinants already dispersed throughout the hospital and associated healthcare facilities. While antibiotic use in hospitals clearly constitutes a stimulus for the emergence of resistance, it is by no means the only important factor. The incorporation of resistance determinants into potentially stable genetic structures, including bacteriophages, plasmids, transposons, and the more newly discovered movable elements termed integrons and gene cassettes, forces some degree of skepticism about the potential for such strategies in institutions where resistance determinants are already prevalent. In particular, the expanding role of integrons may pose an ultimate threat to formulary manipulations such as cycling. Despite these concerns, the crisis posed by antimicrobial resistance warrants investigation of any strategy with the potential for reducing the prevalence of resistance. Over the next decade, new studies with carefully designed outcomes should determine the utility of antibiotic cycling as one control measure for nosocomial resistance.

Before the development of the first antimicrobial agents, bacteria already had demonstrated an ability to adapt to stress in the environment, resulting in the development of resistance that often makes the prevailing antibiotic treatment ineffective. The response to antimicrobial resistance in the medical community has been to use new or alternative antibiotics not previously used against the resistant bacteria. The pharmaceutical industry has responded to the resistance problem by producing newer antibiotics, either as modifications of currently existing compounds or as combinations of compounds that may inhibit or bypass the bacterial resistance mechanisms. The development of new antibiotics is a lengthy and costly process. To be successful, the pharmaceutical industry must anticipate the changing needs of the medical community, as well as the dynamic process of antimicrobial resistance. The marketing of new antimicrobial agents must be adaptable to the potential environmental pressures that induce bacterial resistance in order to ensure the longevity of the agents.

Resistant bacteria usually are seen first in the intensive care unit and other acute-care areas. Thus, strategies to control these organisms often are first tested in these healthcare settings. Frequent among these strategies are attempts to improve antimicrobial use. One proposed method to decrease resistance in special settings like the intensive care unit is the cycling or rotation of antimicrobials. This intervention must be evaluated in the context of other concomitant attempts to improve antimicrobial usage and must take into account other factors influencing resistance.

Until such studies are done, the value of cycling and other efforts to limit prescribers' choices of drugs in endemic settings will be unclear. Studies to evaluate cycling will have to be of large scale to produce useful data. It is unlikely that many hospitals or healthcare systems will have sufficient resources on their own to develop studies of sufficient power to be applied widely. Thus, cooperative studies to provide data on this important issue should be an international priority.